1-(3-Phenylpropyl)-4-(beta-alkoxyacryloyl)piperazine derivatives

ABSTRACT

The present invention relates to novel compounds of piperazine derivatives, which are useful as anesthetics, and to processes for producing the same.

DETAILED DESCRIPTION OF THIS INVENTION

The present invention relates to novel derivatives of 1-(3-phenylpropyl)-4-(β-alkoxyacryloyl)piperazine and acid addition salts thereof, as well as to processes for their preparation.

More particularly, the present invention relates to compounds having the general formula [I] ##STR1## [wherein R₁ and R₂ represent hydrogen atom or lower alkyl group (R₁ and R₂ often represent the same alkyl group but not hydrogen atom at the same time), R₃ represents hydrogen atom or lower alkyl group, R represents lower alkyl group], and acid addition salts thereof, and to processes for producing the same.

The term "lower alkyl group" includes straight and branched chain groups containing from one to six carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group.

According to the present invention, the useful compounds can be prepared as follows. Namely, piperazine derivative [II] may be reacted with acrylic acid derivative [III] to provide a compound of the general formula [I] [wherein R, R₁, R₂ and R₃ have the same meanings given above]. ##STR2##

Of the derivatives of β-alkoxyacrylic acid, the acid chloride is the most effective for the purpose. As solvents which are suitable for the reaction may be named benzene, toluene, chloroform, dichloromethane, diethyl ether. As dehydrohalogenating agents may be named triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, though the reaction proceeds in the absence of dehydrohalogenating agent. The reaction can be carried out at various temperatures and preferably at 0°-50° C.

The acid addition salts of [I] can be prepared by the reaction with non-toxic mineral or organic acids.

A compound of [I] has nothing less than one asymmetric carbon, therefore, general formula [I] contains optical isoners. Moreover, general formula [I] contains all stereoisomers which are derived from combination of two asymmetric carbon atoms, if any.

The compounds included in this invention are useful as general anesthetics. The compound of Example 1 (KA-100), for instance, shows a good anesthetic effect in mice, rats and rabbits. The comparisons between 50% anesthetic dose and 50% lethal dose in mice and rats are given in the following table.

    ______________________________________                                                            AD.sub.50 *                                                                               LD.sub.50 **                                                                            LD.sub.50                               Animals                                                                               Drugs       (mg/kg, i.v.)                                                                             (mg/kg, i.v.)                                                                           AD.sub.50                               ______________________________________                                         mouse  KA-100      7.6        37.3     4.9                                     mouse  Thiopental-Na                                                                              20.9       90.9     4.3                                     rat    KA-100      4.8        60.25    12.6                                    rat    Thiopental-Na                                                                              10.7       80.3     7.5                                     ______________________________________                                          *50% anesthetic dose;                                                          **50% lethal dose                                                        

In rabbits, KA-100 caused an anesthesia at the doses of more than 10 mg/kg (i.v.), and the sleeping times at 20 and 30 mg/kg were 20 min. and more than 20 min. respectively.

Thiopental-Na caused an anesthesia lasted for 13 min. after injection of 20 mg/kg and 30 min. after 30 mg/kg. The recovery of rabbits from ataxic state in post-anesthetic period was far more rapid after treatment with KA-100 as compared with thiopental-Na, although pharmacological potencies of both drugs were practically equal. When rabbits were anesthetized with more than 20 mg/kg of KA-100, they lost the withdrawal reflex against nociceptive stimuli (pinching of hind leg toes by a forceps or small incision of abdomen) and against extension of hind legs. These results suggest that KA-100 has anti-nociceptive and muscular relaxant activity. On the other hand, thiopental-Na caused no anti-nociceptive effect and induced muscular rigidity of the same doses with KA-100 in rabbits.

The maleate of KA-100 is soluble in water at nearly physiological pH (pH 6), and does not disturb blood vessels. KA-100 is a novel useful general anesthetic agent with desirable analgesic and muscular relaxant effects, being different from so far widely used intravenous general anesthetics.

The preparation of these compounds is described in the following examples. It is to be understood, however, that the examples are illustrative of the compounds included by this invention and methods for their preparation and are not to be construed as limiting the invention to the particular compounds or methods specifically described.

EXAMPLE 1 Synthesis of trans-1-(3-phenylpropyl)-2,5-dimethyl-4-(β-ethoxyacryloyl)piperazine maleate

To a solution of trans-1-(3-phenylpropyl)-2,5-dimethyl-piperazine (56g) in benzene (1l) was added dropwise β-ethoxyacryloyl chloride (37g), and the reaction mixture was stirred at room temperature for 30 min., and was added an aqueous solution of potassium carbonate. After stirring for 30 min., benzene layer was separated, washed with water, dried, and concentrated to give oily product. An ethyl acetate solution of the oily product was added to a solution of maleic acid (14.6g) in ethyl acetate, and crystals separated gradually, which were recrystallized from ethyl acetate to give 92g (yield 86%) of colorless needles, melting point 110°-112° C.

Analysis, Calcd for C₂₄ H₃₄ N₂ O₆ : C, 64.55; H, 7.68; N, 6.27. Found : C, 64.63; H, 7.78; N, 6.12.

EXAMPLE 2 Synthesis of trans-1-(3-phenylpropyl)-2,3-dimethyl-4-(β-ethoxyacryloyl)piperazine

To a solution of trans-1-(3-phenylpropyl)-2,3-dimethyl-piperazine (2.3g) in 100 ml of benzene was added dropwise β-ethoxyacryloyl chloride (2g), and the reaction mixture was stirred for 30 min., and was added an aqueous solution of potassium carbonate. After stirring for 30 min., benzene layer was separated, washed with water, dried, and evaporated. The residue was purified by column chromatography to give 3g (yield 90% of oily product.

Analysis, Calcd for C₂₀ H₃₀ N₂ O₂ : C, 72.69; H, 9.15; N, 8.48. Found : C, 72.43; H, 9.38; N, 8.26.

The novel compounds of example 3 to 19 prepared by the methods of Example 1 and 2 are shown in the Table.

    __________________________________________________________________________      ##STR3##                                                                                                          Calcd                                      No. of                                                                              Substituent        Molecular                                                                             M.P. Analysis Found                             Example                                                                              R.sub.1                                                                            R.sub.2                                                                            R.sub.3                                                                            R      formula                                                                              ° C.                                                                         C% H% N%                                   __________________________________________________________________________      3*  2-CH.sub.3                                                                         5-CH.sub.3                                                                         m-CH.sub.3                                                                         C.sub.2 H.sub.5                                                                       C.sub.25 H.sub.36 N.sub.2 O.sub.6                                                     118-120                                                                             65.19                                                                             7.88                                                                              6.08                                                                     64.87                                                                             7.96                                                                              6.00                                  4*  2-CH.sub.3                                                                         5-CH.sub.3                                                                         p-CH.sub.3                                                                         C.sub.2 H.sub.5                                                                       C.sub.25 H.sub.36 N.sub.2 O.sub.6                                                     126-129                                                                             65.19                                                                             7.88                                                                              6.08                                                                     64.88                                                                             7.96                                                                              5.95                                  5   3-CH.sub.3                                                                         H   H   C.sub.2 H.sub.5                                                                       C.sub.23 H.sub.32 N.sub.2 O.sub.6                                                     131-133                                                                             63.87                                                                             7.46                                                                              6.48                                                                     63.89                                                                             7.62                                                                              6.20                                  6** 3-CH.sub.3                                                                         5-CH.sub.3                                                                         H   C.sub.2 H.sub.5                                                                       C.sub.24 H.sub.34 N.sub.2 O.sub.6                                                     155-157                                                                             64.55                                                                             7.68                                                                              6.27                                                                     64.35                                                                             7.83                                                                              5.99                                  7   3-C.sub.2 H.sub.5                                                                  H   H   C.sub.2 H.sub.5                                                                       C.sub.24 H.sub.34 N.sub.2 O.sub.6                                                     121-123                                                                             64.55                                                                             7.68                                                                              6.27                                                                     64.53                                                                             7.80                                                                              6.12                                  8   3-CH.sub.3                                                                         H   p-CH.sub.3                                                                         C.sub.2 H.sub.5                                                                       C.sub.24 H.sub.34 N.sub.2 O.sub.6                                                     132-133                                                                             64.55                                                                             7.68                                                                              6.27                                                                     64.51                                                                             7.76                                                                              6.10                                  9*  2-CH.sub.3                                                                         5-CH.sub.3                                                                         H   C.sub.2 H.sub.5                                                                       C.sub.20 H.sub.30 N.sub.2 O.sub.2                                                     oil  72.69                                                                             9.15                                                                              8.48                                                                     72.50                                                                             9.40                                                                              8.35                                 10** 2-CH.sub.3                                                                         3-CH.sub.3                                                                         H   C.sub.2 H.sub.5                                                                       C.sub.24 H.sub.34 N.sub.2 O.sub.6                                                     155-157                                                                             64.55                                                                             7.68                                                                              6.27                                                                     64.38                                                                             7.68                                                                              6.01                                 11** 3-CH.sub.3                                                                         5-CH.sub.3                                                                         H   CH.sub.3                                                                              C.sub.23 H.sub.32 N.sub.2 O.sub.6                                                     168-169                                                                             63.87                                                                             7.46                                                                              6.48                                                                     63.71                                                                             7.58                                                                              6.35                                 12*  2-CH.sub.3                                                                         5-CH.sub.3                                                                         H   CH.sub.3                                                                              C.sub.23 H.sub.32 N.sub.2 O.sub.6                                                     133-134                                                                             63.87                                                                             7.46                                                                              6.48                                                                     63.60                                                                             7.60                                                                              6.23                                 13*  2-CH.sub.3                                                                         3-CH.sub.3                                                                         H   CH.sub.3                                                                              C.sub.19 H.sub.28 N.sub.2 O.sub.2                                                     oil  72.11                                                                             8.92                                                                              8.85                                                                     71.86                                                                             9.11                                                                              8.59                                 14** 3-CH.sub.3                                                                         5-CH.sub.3                                                                         H   CH.sub.2 CH.sub.2 CH.sub.3                                                            C.sub.25 H.sub.36 N.sub.2 O.sub.6                                                     133-134                                                                             65.20                                                                             7.88                                                                              6.08                                                                     64.98                                                                             8.00                                                                              5.83                                 15*  2-CH.sub.3                                                                         3-CH.sub.3                                                                         H   CH.sub.2 CH.sub.2 CH.sub.3                                                            C.sub.25 H.sub.36 N.sub.2 O.sub.6                                                     90-91                                                                               65.20                                                                             7.88                                                                              6.08                                                                     65.19                                                                             8.03                                                                              5.99                                 16*  2-CH.sub.3                                                                         5-CH.sub.3                                                                         H   CH(CH.sub.3).sub.2                                                                    C.sub.25 H.sub.36 N.sub.2 O.sub.6                                                     87-90                                                                               62.50                                                                             7.88                                                                              6.08                                                                     64.90                                                                             7.99                                                                              5.93                                 17** 3-CH.sub.3                                                                         5-CH.sub.3                                                                         H   CH(CH.sub.3).sub.2                                                                    C.sub.25 H.sub.36 N.sub.2 O.sub.6                                                     163-166                                                                             65.20                                                                             7.88                                                                              6.08                                                                     64.96                                                                             8.03                                                                              5.91                                 18*  2-CH.sub.3                                                                         3-CH.sub.3                                                                         H   CH(CH.sub.3).sub.2                                                                    C.sub.21 H.sub.32 N.sub.2 O.sub.2                                                     oil  73.21                                                                             9.36                                                                              8.13                                                                     72.92                                                                             9.61                                                                              8.04                                 19** 3-CH.sub.3                                                                         5-CH.sub.3                                                                         H   n-butyl                                                                               C.sub.26 H.sub.38 N.sub.2 O.sub.6                                                     118-119                                                                             65.80                                                                             8.07                                                                              5.90                                                                     65.58                                                                             8.21                                                                              5.77                                 __________________________________________________________________________       *trans form,                                                                   *cis form                                                                

What is claimed is:
 1. The compound trans- 1-(3-Phenylpropyl)-2,5-dimethyl-4-(β-ethoxyacryloyl)piperazine.
 2. The compound trans-1-(3-Phenylpropyl)-2,3-dimethyl-4-(β-ethoxyacryloyl)piperazine.
 3. The compound trans-1-(3-m-Methylphenylpropyl)-2,5-dimethyl-4-(β-ethoxyacryloyl)piperazine.
 4. The compound trans-1-(3-p-Methylphenylpropyl)-2,5-dimethyl-4-(β-ethoxyacryloyl)piperazine.
 5. The compound 1-(3-Phenylpropyl)-3-methyl-4-(β-ethoxyacryloyl)piperazine.
 6. The compound cis-1-(3-Phenylpropyl)-3,5-dimethyl-4-(β-ethoxyacryloyl)piperazine.
 7. The compound 1-(3-Phenylpropyl)-3-ethyl-4-(β-ethoxyacryloyl)piperazine.
 8. The compound 1-(3-p-Methylphenylpropyl)-3-methyl-4-(β-ethoxyacryloyl)piperazine.
 9. The compounds trans-1-(3-Phenylpropyl)-2,5-dimethyl-4-(β-ethoxyacryloyl)piperazine.
 10. The compound cis-1-(3-Phenylpropyl)-2,3-dimethyl-4-(β-ethoxyacryloyl)piperazine.
 11. The compound cis-1-(3-Phenylpropyl)-3,5-dimethyl-4-(β-methoxyacryloyl)piperazine.
 12. The compound trans-1-(3-Phenylpropyl)-2,5-dimethyl-4-(β-methoxyacryloyl)piperazine
 13. The compound trans-1-(3-Phenylpropyl)-2,3-dimethyl-4-(β-methoxyacryloyl)piperazine
 14. The compound cis-1-(3-Phenylpropyl)-3,5-dimethyl-4-(β-n-propoxyacryloyl)piperazine.
 15. The compound trans-1-(3-Phenylpropyl)-2,3-dimethyl-4-(β-n-propoxyacryloyl)piperazine.
 16. The compound trans-1-(3-Phenylpropyl)-2,5-dimethyl-4-(β-isopropoxyacryloyl)piperazine.
 17. The compound cis-1-(3-Phenylpropyl)-3,5-dimethyl-4-(β-isopropoxyacryloyl)piperazine.
 18. The compound trans-1-(3-Phenylpropyl)-2,3-dimethyl-4-(β-isopropoxyacryloyl)piperazine.
 19. The compound cis-1-(3-Phenylpropyl)-3,5-dimethyl-4-(β-n-butoxyacryloyl)piperazine. 